Abstract PS1-09-02: Intracranial activity of datopotamab deruxtecan (Dato-DXd) for patients with HER2-negative breast cancer and leptomeningeal disease (LMD): Results from Cohort C of the DATO-BASE phase 2 trial

Abstract Background: LMD represents a rare but devastating manifestation of metastatic breast cancer (MBC), with a significant unmet need for effective treatments. Datopotamab deruxtecan (Dato-DXd) is a TROP2-directed antibody-drug conjugate (ADC) that has demonstrated promising activity for HER2-negative MBC and clinical evidence of central nervous system (CNS) activity in patients with lung cancer. Methods: DATO-BASE (NCT06176261) is a multicenter, multicohort, single-arm, phase II trial enrolling patients with HER2-negative MBC and active CNS disease. Cohort C was an exploratory cohort enrolling patients with HER2-negative MBC and LMD, either newly diagnosed or progressive. Prior systemic therapy for LMD and prior ADCs were permitted. Patients received Dato-DXd 6 mg/kg IV every 3 weeks until progression, unacceptable toxicity, or withdrawal. Exploratory endpoints include overall survival (OS), radiographic and clinical response according to LANO (Leptomeningeal Assessment in Neuro-Oncology) criteria, intracranial progression-free survival (PFS), safety, quality of life, neurological function according to the NANO (Neurological Assessment in Neuro-Oncology) scale and biomarker analyses. Sections from archival tissue samples were stained for HER2 and TROP2 using the TROPLEX quantitative immunofluorescence assay, to obtain high-sensitivity (HS)-Trop2 and HS-HER2 expressions (attomoles/mm2). Results: A total of 10 patients with LMD were enrolled, of which 9 also had extracranial disease. Median age was 49 years (range 40 - 76), 8 patients had hormone receptor-positive disease and 2 had triple-negative disease; 60% had HER2-low disease. Eight patients had received prior local therapy for CNS disease (3 surgery, 2 surgery and stereotactic radiation, 3 whole-brain radiation). Patients had a median of 2.5 (range 0-6) prior lines of cytotoxic treatment, with 7 who had received prior ADCs (3 T-DXd, 2 SG, 2 both ADCs). Response rate by LANO criteria was 30% (n=3/10), with two partial responses in ADC-naive patients and one complete response in an ADC-pretreated patient (prior SG). With a median follow up of 8.1 months, the median intracranial PFS was 4.1 months (95% CI: 0.7 to not reached), and median OS was 4.7 months (95% CI: 0.7 to not reached). ADC-naïve patients (n=3) experienced numerically longer intracranial PFS (5.9 vs 1.4 months), and longer OS (13.3 vs 3.7 months) compared with ADC-pretreated patients. TROPLEX data was available for 8 patients, including two responders. All patients had HS-Trop2-high disease, whereas only 50% had HS-HER2-high disease. One LANO response each was observed in patients with HS-Trop2 > median and HS-Trop2 ≤ median, with the two groups showing a median intracranial PFS of 4.67 months vs 4.11 months, respectively. Similarly, one LANO response each was observed in patients with HS-HER2 > median and HS-HER2 ≤ median. Grade ≥2 treatment-related adverse events (TRAEs) occurred in 70% (n=7/10) of the patients, with the most common being stomatitis (40%, n=4), fatigue (30%, n=3) and nausea (30%, n=3); only one grade 4 TRAE was observed (dyspnea). No patient experienced interstitial lung disease nor grade 5 TRAEs. Out of 7 patients who had neurological symptoms at baseline according to the NANO score, improvement in at least one symptom was observed in 5 patients, with 1 patient showing stable symptoms and 1 patient missing follow up NANO assessment. Conclusions: In this exploratory cohort of DATO-BASE, Dato-DXd demonstrated promising intracranial activity in patients with HER2-negative MBC and LMD, including radiographic responses and improvement in neurological symptoms in most patients with baseline deficits. Outcomes appeared more favorable in ADC-naïve patients, although numbers were limited. Citation Format: P. Tarantino, N. Zhou, T. Li, E. Kelly, C. Strickland, N. Chan, M. DeMeo, L. Anderson, E. Pasternak, C. Anders, M. Ahluwalia, R. Mahtani, L. Hsu, S. Ossing, A. Waks, C. Block, A. Garrido-Castro, S. Schumer, I. Schlam, D. Rimm, N. Tayob, S. M. Tolaney, N. U. Lin, S. Sammons. Intracranial activity of datopotamab deruxtecan (Dato-DXd) for patients with HER2-negative breast cancer and leptomeningeal disease (LMD): Results from Cohort C of the DATO-BASE phase 2 trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-09-02.